Although the physiological mechanism is not completely understood, it has been reported that animals placed on a purified, chromium-free diet for several weeks displayed greatly impaired glucose tolerance, i.e. the ability to maintain blood glucose at normal levels. It was found that a diet containing Brewer's yeast would eliminate this impairment and blood glucose levels would return to normal.
The presence of chromium as an organic salt in foods was also found to increase glucose oxidation in humans, particularly when extracts of Brewer's yeast containing chromium were added. In addition, oral administration of such material to a diabetic individual was found to influence the pancreas to produce normal amounts of insulin.
The relationship of chromium content in food and its effects on glucose oxidation activity are discussed, for example, in Toepfer, et al., "Chromium Foods in Relation to Biological Activity," J. Agr. Food. Chem. 21:69 (1973).
These and other findings led to an interest in Brewer's yeast as a source of a naturally occurring glucose tolerance factor (GTF) by early workers in the field of trace mineral research. A discussion of the history of GTF research can be found in McCarthy, et al., "High-Chromium Yeast and Glucose Tolerance Factor," J. Prevention Medicine 2 (1983). Considerable research has been directed towards concentrating the chromium content of Brewer's yeast to a commercially feasible amount. See, for example, U.S. Pat. No. 4,343,905.
Glucose tolerance factor is believed to be a complex of trivalent chromium with two moles of nicotinic acid (niacin) and at least one mole of an amino acid. For example, as suggested by Mertz, et al. in "Present Knowledge of the Role of Chromium," Fed. Proc. 33(11):2275-2280 (1974), it is possible that the structure for natural GTF could be derived from the structure for a tetraaquo-dinicotinato Cr-complex, i.e., ##STR1## wherein the molecules of water are replaced by amino acid ligands.
Thus, although the exact structure of GTF is not known at this time, one possible structure might be as follows: ##STR2##
Alternatively, a recent patent application, published as WO 87/03200, reports the isolation and purification from yeast of a compound with GTF activity which is a quinoline derivative having a molecular weight of 174 and a structural formula as follows: ##STR3## wherein at least one R group is hydrogen and the two non-hydrogen, non-identical R groups are --OCH.sub.3 or --NH.sub.2. This report includes reference to additional research efforts which cast doubt on the role of chromium and chromium-nicotinic acid-amino acid complexes in yeast GTF activity.
Attempts have also been made to synthesize trace metal complexes which exhibit GTF activity. For example, U.S. Pat. No. 4,242,257 discloses a material exhibiting GTF activity which is obtained by complexing cobalt with nicotinamide in a ratio of 1:2, followed by acidification of the complex and reduction with glutathione. Similarly, the synthesis of chromium-nicotinic acid complexes, which exhibit GTF activity, by refluxing chromium chloride in alcohol for periods of up to about 16 to 24 hours with nicotinic acid and several amino acids has been disclosed. See, for example, Toepfer, et al., "Preparation of Chromium-Containing Material of Glucose Factor Activity from Brewer's Yeast Extracts and by Synthesis", J. Agr. Food Chem. 25(1):162-166 (1977).
There has also been a report of a green chromium complex with pyridine-3-carboxylic acid (nicotinic acid) which was soluble in common organic solvents, including water, acetone, etc. Chatterjee, B., "Donor Properties of Pyridine and Quinoline Carboxylic Acids: Pyridine and Quinoline Carboxylato Complexes of Chromium(III)," J. Indian Chem. Soc. 53:1212-1213 (1976). The report does not disclose any use for the complex.
While the prior art techniques of extracting and/or concentrating chromium GTF from Brewer's yeast have been reasonably successful, the required processing normally is rather complex. This makes the product expensive when used for chromium supplementation of chromium deficient diets or for individuals otherwise requiring chromium supplementation. This problem has not been overcome by synthetically prepared GTF materials because, for the most part, synthetic GTF materials are of limited activity, are formed in relatively poor yields, and/or are highly unstable.
Accordingly, it is an object of the present invention to produce a synthetic GTF material which is stable over extended periods of time.
It is another object of the invention to produce a synthetic GTF chromium complex which can be easily prepared in high yields under relatively mild conditions.
Yet another object of the invention is to produce a non-polar chromium GTF material which would be transported actively at the sites of absorption of nicotinic acid.
Still another object is to provide a chromium GTF material which can be modified easily by an individual's metabolic system to the appropriate isomeric form, or which exhibits biological activity on its own without need for any such modification.
Another object is to prepare a chromium GTF material which is yeast-free and which does not require the use of yeast in its synthesis.